Obesity is a major contributor to serious health problems. The incidence of obesity within the US has soared during the last 30-40 years, with a contributing cause being the increased consumption of high-fat foods. Diets high in fat can result in overeating (hyperphagia), which promotes obesity in susceptible individuals. There is evidence in both humans and rats that hyperphagia is related to reduce sensitivity to the satiating effect of dietary fat, due to reduced engagement of brainstem satiety circuits. The proposed research will further elucidate the functional organization of these circuits, highlightin a potentially critical role for hindbrain noradrenergic neurons that co-express prolactin-releasing peptide (PrRP). The proposed work is consistent with the NIH Strategic Plan for Obesity Research by its focus on physiological neural mechanisms that regulate food intake and body weight. Animal models can provide critical insights into physiological and behavioral factors that predispose humans to become obese. Further, PrRP neurons are located within human caudal brainstem in a distribution similar to that in rodent species. Thus, experimental outcomes will have translational implications for understanding how dietary fat promotes overeating in humans who are susceptible to diet-induced hyperphagia, while others exposed to the same diet remain relatively resistant. We propose that behavioral satiety is generated, at least in part, by recruitment of PrRP-positive neurons in the caudal visceral portion of the nucleus of the solitary tract, and that these neurons are polysynaptically linked to brainstem oral ingestive control motor neurons. PrRP neurons receive direct visceral sensory input from gastrointestinal vagal afferents, and central PrRP signaling is implicated in the homeostatic control of food intake in rats and mice. The proposed research will use adult male rats to challenge the overarching hypothesis that satiety signals recruit brainstem PrRP signaling pathways that limit meal size. In addition, we will test the hypothesis that a high-fat diet attenuates this natural PrRP-mediated satiety process in individual rats that develop hyperphagia, but not in resistant rats. We propose that increased consummatory responses to high fat diet are due, at least in part, to attenuated satiety signal-induced recruitment of brainstem PrRP neurons that act to limit food intake. Outbred Sprague-Dawley rats are an ideal experimental model for the proposed research, because approximately 50% develop behavioral hyperphagia (i.e., increased meal size and daily food intake) that promotes increased body weight gain during high fat diet exposure, whereas the remainder are resistant, and do not increase their daily intake or BW more than they do on normal control diet.